Through our ongoing integrative neuroimaging studies of a unique and growing cohort of medication-free patients with schizophrenia, our group continues to make progress toward its goals of understanding the nature, molecular underpinnings, underlying neurochemistry, and clinical correlates of neural systems-level dysfunction in this devastating illness. As we describe in extensive detail in Eisenberg and Berman (Neuropsychopharmacology, 2010), critical disturbances in cognitive control neural circuitry in schizophrenia not only serve as sources of marked disability in affected individuals, but also provide a valuable phenotype for testing hypotheses regarding how genes implicated in schizophrenia might contribute risk. For example, by measuring regional cerebral blood flow during the N-back continuous working memory task, we have re-confirmed an aberrant prefrontal activation pattern even in patients who perform relatively well on the task and further demonstrated profoundly aberrant connectivity in prefrontal and medial temporal lobe regions, which showed strong ability to discriminate between healthy and ill participants. This latter finding was prospectively validated in two additional data sets, suggesting that disturbances in the prefrontal-limbic functional axis may be an illness trait marker. We now have extended this work even further, reporting on a unique gene-diagnosis interaction operating on regional cerebral blood flow involving the gene coding for catechol-O-methyltransferase, COMT, which harbors common variation that is weakly but consistently associated with schizophrenia risk and strongly implicated in both prefrontal and limbic functioning during executive and affective challenge, respectively, in healthy individuals. In particular, we have identified that even at rest there exists in patients with schizophrenia an inverse relationship between dorsolateral prefrontal cortical and medial temporal lobe blood flow, which is mediated by COMT genotype. This is an effect not seen in healthy study participants and suggests an important intersection between genetically determined cortical dopaminergic tone and fundamental biases in baseline prefrontal-limbic neural network activity in patients suffering with schizophrenia. This study therefore elucidates a mechanistic explanation for variation in characteristic resting-state neural abnormalities previously identified in schizophrenia. In parallel with advancing our neuroimaging genetic efforts, we have now made a substantial expansion to our cross-modal neuroimaging studies in schizophrenia to include comprehensive positron emission tomographic (PET) assessment of the dopaminergic synapse. Previously, we have demonstrated the power of cross-modal approaches by determining both presynaptic dopamine (measured by 18F-DOPA PET) and executive function related neural activation (measured by 15O-water PET during the Wisconsin Card Sorting Task) in patients and healthy controls to show not only exaggerated striatal FDOPA uptake and impaired prefrontal activation in patients, but also, and more importantly, a highly significant negative correlation between task-related prefrontal activation and striatal dopamine uptake in patients but not controls. This study provided a crucial basis for the coexistence of two key pathophysiological hallmarks of schizophrenia.